1. Field of the Invention
The present invention relates to the synthesis and preparation of high molecular weight polyanhydrides suitable for use as bioerodible sustained drug release devices. More particularly, the present invention pertains to a sustained drug release implant formed from a thin film of a homogeneous matrix of the novel high molecular weight polyanhydrides and a suitable drug. The novel high molecular weight polyanhydride implants exhibit superior biocompatibility, release and degradation rates without experiencing any polymer to drug interaction. The novel polyanhydrides further exhibit increased chemical stability and have demonstrated superior film forming qualities enabling the polyanhydrides to be used with solvent casting techniques.
2. Description of the Prior Art
In recent years much research has been carried out to develop systems for the controlled release of active agents, especially drugs, over a period of time. In conventional drug delivery, proceeding through various routes of administration, one characteristically sees drug concentration in plasma rise, reach a maximum and fall. The problems encountered with these conventional drug delivery systems include the danger of reaching toxic levels where serious side effects can occur, and conversely the danger of drug concentrations falling to the subtherapeutic level. Efforts to address these problems date to as early as the 1930's, when the concept of sustained drug delivery was introduced in an effort to control the rate of release and maintain a continuous level of drug within the patient.
The purpose of these controlled release systems is to prolong the release of the drug at a controlled constant rate. By controlling the rate of release of the drug the therapeutic effects of the drug are thereby maximized by presenting the drug in a continuous, most beneficial and reliable manner with a minimum possibility of complications due to the fluctuating drug concentration.
The controlled release of drugs can be accomplished by several mechanisms including the complexation with substances such as salts or resins, formation of emulsions or suspensions, compression into dense matrices, and encapsulation using coatings whose dissolution is pH dependent. While such systems have been effective in prolonging drug release, they in general suffer from patient to patient variations and an inability to provide release for periods of time greater than one day. Bioerodible implants offer controlled release of drugs avoiding the disadvantages of the prior art drug release systems while offering the additional advantage of eliminating the need for surgical removal of the device.
The bioerodible drug release systems which have proven most effective are the devices where the drug is uniformly distributed throughout the polymer in a homogeneous matrix. In addition, effective bioerodible systems require that the surface erosion is the only determining factor permitting the drug release to occur. With a constant erosion rate the rate of release of the drug is proportional to the surface area of the system. Preferably the polymeric matrix erodes at a constant preselected rate, with only minimal diffusion, such that the drug is released independently of the concentration of any other chemical component or stimulus. It is therefore necessary to utilize a geometry of the polymeric matrix that does not substantially change its surface area as a function of time in order to obtain zero order release of the drug.
To be useful as a matrix for controlled drug release the polymeric composition must also not undergo bulk erosion which often occurs in addition to or in place of surface erosion. This bulk erosion causes the composition to take on a sponge-like consistency which causes the break-up of the polymeric matrix. Bulk erosion has been shown to directly result from the hydrophilic nature of most bioerodible polymeric compositions. Examples of polymeric matrices which have been shown to undergo bulk erosion include polylactic acid, polyglutamic acid, polycaprolactone and lactic/glycolic acid copolymers.
One example of the prior art bioerodible drug release polymers employs a polyorthoester composition as described in U.S. Pat. No. 4,070,347. An advantage of the use of polyorthoesters is that hydrolysis of the polymer is pH sensitive and the pH may therefore be used for regulation of the release of the drug. In practice however, the polyorthoesters which have been synthesized have numerous disadvantages which have hindered their use. For example polyorthoesters are often times too hydrolytically stable for use in controlled release systems without acid catalysts being included within the polymeric matrix to promote bioerosion. As a consequence, the polyorthoester polymers tend to swell substantially when attempts are made to suppress degradation in the interior of the matrix. The rate of swelling of the polymer often dominates and affects the rate of release of the drug more than the rate of erosion itself. Additionally, the degradation products are not as simple as some other bioerodible polymers such as polylactic acid which has the advantage of degrading into water and carbon dioxide.
A further example of the prior art controlled drug release devices is described in a recent study by Leong, et al reported in J. Biomed. Mat. Res.. Vol. 19, 941-955 (1985). These controlled release devices incorporated a low molecular weight polyanhydride copolymer prepared from mixed prepolymers. Controlled studies have shown that the prior art polyanhydrides produced by known solution polymerization and melt polymerizations to have a weight average molecular weight of a few thousand up to at most 20,000. These prior art polyanhydrides have been limited in their utility as bioerodible implants due to their low molecular weight (generally 12,500) and correspondingly low intrinsic viscosity in solution (approximately 0.1 to 0.3 dl/g in organic solvents at room temperature). Although the prior art polyanhydrides are useful in controlled release drug delivery systems due to their hydrolytic instability and the fact that they degrade into monomeric diacids which are biocompatible as shown by tissue response and toxicological studies, the rate of degradation is too rapid for many applications. In addition, these prior art low molecular weight polyanhydrides have been found to degrade at a rate greater than the rate of release of the drug and begin to disintegrate after approximately 60 percent degradation.
Further disadvantages of the prior art low molecular weight polyanhydrides is the low tensil strength and poor film forming qualities such that the use of low molecular weight polyanhydrides results in a polymeric matrix which is opaque, brittle and incapable of being formed into thin disks or films. Because of the physical limitations of the low molecular weight polyanhydrides the controlled release devices can only be manufactured by pressing the powdered polyanhydride with the drug into a tablet or by melting the polyanhydride with the drug at a relatively high temperature. The first method frequently results in a nonhomogeneous mixture which demonstrates poor release kinetics. Melting the two components tends to cause degradation of the drug and interactions between the drugs and the polyanhydrides.
The generally preferred method of manufacturing biomedical devices is by solvent casting the polymeric material to form films. These films have the advantage of generally providing a more homogeneous distribution of the drug and the ability to be cast as a sheet at ambient temperature thereby providing more desirable release kinetics for the controlled release of the drug. The prior art low molecular weight polyanhydrides, due to their brittle characteristics, low tensil strength, and low viscosity have proven unsatisfactory for such solvent casting techniques.
Other examples of the prior art polyanhydrides are reported J. Am. Chem. Soc., Vol. 52, 4110 (1930) and J. Am. Chem. Soc., Vol. 54, 1569 (1932). Examples of such prior art polymers include poly [bis(p-carboxyphenoxy)alkane anhydrides] which exhibit improved hydrolytic resistance as well as film and fiber forming properties as reported in Makromol. Chem., Vol. 24, 76 (1957). These prior art polyanhydrides have the disadvantage in that they tend to be insoluble in organic solvents, have a low tensil strength and viscosity and thus cannot be solvent cast. Although over 100 different polyanhydrides have been prepared to date, these polyanhydrides have never been commercialized primarily due to the problem of hydrolytic instability.
Some of the prior art polyanhydrides are reported to have molecular weights as high as 20,000 while other prior art polyanhydrides have been reported to have an intrinsic viscosity greater than 0.3 dl/g. The polyanhydrides when prepared according to these disclosed methods seldom produce a high molecular weight having a weight average molecular weight greater than 20,000 or an intrinsic viscosity greater than 0.3 dl/g. The prior art polyanhydrides reported to have the higher molecular weights had a low intrinsic viscosity while those which exhibited the higher intrinsic viscosities had the lower molecular weights. None of the prior art polyanhydrides when prepared according to the disclosed method have been shown to simultaneously have both a weight average molecular weight greater than 20,000 and an intrinsic viscosity greater than 0.3 dl/g. As setforth hereafter in greater detail the combination of both of these characteristics affect the film forming characteristics of the polyanhydrides and it is believed the poor film forming qualities of the prior art polyanhydrides is due to the lower molecular weight and intrinsic viscosity.
There is thus a need for a hydrophobic bioerodible polymeric system capable of providing controlled drug release wherein the erosion products are nontoxic and are readily eliminated or metabolized by the body. In addition, it would be desirable to provide a polymeric system which exhibits good mechanical and physical integrity, includes good film forming characteristics to be adaptable for solvent casting and has a high tensil strength. A suitable polymeric matrix for controlled drug release must further be dense enough to prevent diffusion of the drug, be easy to synthesize and be stable for extended periods of time.
The present invention is directed primarily to a controlled release polymeric matrix utilizing a high molecular weight polyanhydride homogeneously mixed with a suitable drug. The high molecular weight polyanhydride used with the controlled release device is capable of being solvent cast into a variety of shapes and sizes. The novel high molecular weight polyanhydrides of the present invention exhibit transparent, flexible and thin film forming capabilities. In addition, the novel high molecular weight polyanhydride matrices are found to possess a higher density increase in the hydrophobicity of the resulting polymer matrix a more constant rate of degradation and drug release and improved biocompatibility than the prior art low molecular weight polyanhydrides.